13-39655706-G-GC

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP6 BS1

The NM_020751.3(COG6):c.-21_-20insC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000243 in 1,486,174 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00092 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00022 (1 hom.)
• Consequence: COG6 NM_020751.3 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -4.32

Genes affected

COG6 (HGNC:18621): (component of oligomeric golgi complex 6) This gene encodes a subunit of the conserved oligomeric Golgi complex that is required for maintaining normal structure and activity of the Golgi apparatus. The encoded protein is organized with conserved oligomeric Golgi complex components 5, 7 and 8 into a sub-complex referred to as lobe B. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Feb 2009]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 13-39655706-G-GC is Benign according to our data. Variant chr13-39655706-G-GC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 312126.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000925 (51/55146) while in subpopulation EAS AF= 0.0069 (11/1594). AF 95% confidence interval is 0.00387. There are 0 homozygotes in gnomad4. There are 26 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COG6	NM_020751.3	c.-21_-20insC		5_prime_UTR_variant	1/19	ENST00000455146.8
COG6	NM_001145079.2	c.-21_-20insC		5_prime_UTR_variant	1/19
COG6	XM_011535168.2	c.-21_-20insC		5_prime_UTR_variant	1/20
COG6	NR_026745.1	n.80_81insC		non_coding_transcript_exon_variant	1/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COG6	ENST00000455146.8	c.-21_-20insC		5_prime_UTR_variant	1/19	1	NM_020751.3	P1

Frequencies

GnomAD3 genomes AF: 0.000944 AC: 52 AN: 55088 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00173

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00208

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00689

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000155

Gnomad OTH AF: 0.00154

GnomAD3 exomes AF: 0.000586 AC: 35 AN: 59716 Hom.: 0 AF XY: 0.000490 AC XY: 16 AN XY: 32622

Gnomad AFR exome AF: 0.00232

Gnomad AMR exome AF: 0.00202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00315

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000331

Gnomad OTH exome AF: 0.000645

GnomAD4 exome AF: 0.000217 AC: 310 AN: 1431028 Hom.: 1 Cov.: 40 AF XY: 0.000231 AC XY: 164 AN XY: 709170

Gnomad4 AFR exome AF: 0.000765

Gnomad4 AMR exome AF: 0.000191

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00617

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000338

Gnomad4 OTH exome AF: 0.000102

GnomAD4 genome AF: 0.000925 AC: 51 AN: 55146 Hom.: 0 Cov.: 34 AF XY: 0.000977 AC XY: 26 AN XY: 26600

Gnomad4 AFR AF: 0.00167

Gnomad4 AMR AF: 0.00208

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00690

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000155

Gnomad4 OTH AF: 0.00155

Bravo AF: 0.000400

Asia WGS AF: 0.00141 AC: 3 AN: 2142

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Congenital disorder of glycosylation Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 22, 2017

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

COG6-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 22, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs746938820; hg19: chr13-40229843;